Alzheimer's disease is a major health problem affecting 4 million persons in the USA. The key to understanding AD is determining the etiology and pathogenesis of neuron degeneration in specific brain regions. This application is for a five year renewal of the Program Project Grant (P01AG05119) at the University of Kentucky (UK) Sanders-Brown Center on Aging. The major goal of this program proje4ct is to gain an understanding of brain oxidation in AD. The program project is composed of two cores and four closely interrelated projects. Each project has human (AD and control), gene-altered animal and cell culture components. Each project has published and preliminary data relevant to specimens from longitudinally followed AD and control subjects that have short post-mortem interval autopsies. Project by Markesbery examines the hypothesis that oxidation of DNA and RNA oxidation. Project by Butterfield is aimed at defining the molecular mechanisms and sequela of Abeta-associated oxidative stress in AD. Special emphasis will be placed on the action of methionine in Abeta (1- 42) in oxidative stress and neuron toxicity. Project by St. Clair examines the hypothesis that the ability of mitochondria to remove superoxide radicals without inflicting self injury plays a central role in regulating free radical mediated neurodegeneration in AD. This study will investigate the mechanism by which increased expression of manganese superoxide dismutase can be safely achieved in the brain. Project by Kindy is designed to understand the interaction between the receptor for advanced glycation endproducts, Abeta and oxidative stress. A coordination and administration Core will provide supervision and coordination of the research projects, financial management, statistical support, internal and external scientific review and procurement of tissue from the Uk ADRC. The Animal Core provides transgenic, knockout and knockin mice for all four projects. This program project has the potential of identifying molecular targets for development of therapeutic agents aimed at decreasing neuron injury and improving the outcome of AD.